- Email: [email protected]
Rheumatology reviews: January–March 2013
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Available online at www.indianjrheumatol.com and www.sciencedirect.com
Rheumatology Reviews
Rheumatology reviews: JanuaryeMarch 2013 Sukhbir Uppal Department of Medicine, University Hospital Sharjah, United Arab Emirates
1.
Rheumatoid arthritis
1.1. Methotrexate use is associated with a 70% reduction in mortality in RA A study to examine the relationship between methotrexate (MTX) use and mortality in RA has been published. This study examined 5626 RA patients prospectively for 25 years to determine the risk of death associated with MTX use. During follow-up, 666 patients (12%) died. MTX use was associated with reduced risk of death (adjusted hazard ratio 0.30). Selective MTX cessation immediately before death did not account for the protective association of MTX use with mortality. Only MTX use for >1 year was associated with lower risks of mortality, but associations were not stronger with longer durations of use. Thus, MTX use is associated with a 70% reduction in mortality in RA (A&R 2013;65:334e342).
1.2. Glucocorticoids are associated with an increased risk of myocardial infarction in RA A study has assessed the effect of glucocorticoids (GCs) on acute myocardial infarction (MI) risk in patients with RA. Using administrative health data, the authors conducted a population-based cohort study of 8384 incident RA cases (1997e2006). Primary exposure was incident GC use. MI events were ascertained using hospitalization and vital statistics data. GC use was modelled as four alternative timedependent variables (current use, current dose, cumulative dose and cumulative duration), adjusting for demographics, comorbidities, cardiovascular drug use, propensity score and RA characteristics. Sensitivity analyses explored potential effects of unmeasured confounding. Within 50,238 person years in 8384 RA cases, 298 incident MI events were identified. Multivariable models showed that current GC use was associated with 68% increased risk of MI [HR ¼ 1.68]. Similarly, separate multivariable models showed that current daily dose (HR ¼ 1.14 per each 5 mg/day increase), cumulative duration
of use (HR ¼ 1.14 per year of GC use) and total cumulative dose (HR ¼ 1.06 per gram accumulated in the past) were also associated with increased risk of MI. Furthermore, in the same multivariable model, current dose and cumulative use were independently associated with an increased risk of MI (10% per additional year on GCs and 13% per 5 mg/day increase). Thus, GCs are associated with an increased risk of MI in RA. The results suggest a dual effect of GCs on MI risk, an immediate effect mediated through current dosage and a long-term effect of cumulative exposure. (Rheumatology 2013;52:68e75).
1.3. DAS28-CRP assessed with 3 and 4 variables in patients with RA should not be used interchangeably in the daily clinic without caution The DAS28-CRP(4) composite measure for RA is based on 4 variables: tender and swollen joint counts, CRP, and patient global assessment. DAS28-CRP(3) includes only 3 variables, because patient global assessment has been omitted. Thresholds for low and high disease activity are the same for the 2 scores. A recent study comparing the 2 DAS scores and their responses on the individual patient level has been reported. Baseline and 12-week disease activity data from 239 patients with RA treated with a biological agent were extracted. Baseline values for DAS28-CRP(4) and DAS28-CRP(3) were 4.8 1.2 and 4.6 1.1, respectively. At 12 weeks, DAS28-CRP(4) had improved by 1.39 1.34 ( p < 0.0001). At that timepoint the bias of DAS28-CRP(3) was 0.07. The bias of the DAS28CRP(3) response was þ0.21. Effect size for DAS28-CRP(4) was 1.2 1.1 versus 1.1 1.1 for DAS28-CRP(3) ( p < 0.0001). Compared to DAS28-CRP(4), DAS28-CRP(3) categorized 33% fewer patients as having a high level of disease activity, 8% fewer patients as good responders, and 12% more patients as nonresponders. Thus, mean values of DAS28-CRP(4) and DAS28-CRP(3) agree well, but in the individual patient the difference between the scores and their responses may be substantial. (J Rheumatol First Release March 1 2013).
E-mail address: [email protected]. 0973-3698/$ e see front matter Copyright ª 2013, Indian Rheumatology Association. All rights reserved. http://dx.doi.org/10.1016/j.injr.2013.04.007
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1.4. Evening low-dose modified release prednisone added to existing DMARD treatment produces rapid and relevant improvements in RA signs and symptoms In order to assess the efficacy and safety of low-dose prednisone chronotherapy using a new modified-release (MR) formulation for the treatment of RA, this 12-week, doubleblind, placebo-controlled study randomized patients with active RA (n ¼ 350) 2:1 to receive MR prednisone 5 mg or placebo once daily in the evening in addition to their existing DMARD treatment. It was found that MR prednisone plus DMARD treatment produced higher response rates for ACR20 (48% versus 29%, p < 0.001) and ACR50 (22% versus 10%, p < 0.006) and a greater median relative reduction from baseline in morning stiffness (55% versus 35%, p < 0.002) at week 12 than placebo plus DMARD treatment. Significantly greater reductions in severity of RA (Disease Activity Score 28) ( p < 0.001) and fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue score) ( p ¼ 0.003) as well as a greater improvement in physical function (36-item Short- Form Health Survey score) ( p < 0.001) were seen at week 12 for MR prednisone versus placebo. The incidence of adverse events was similar for MR prednisone (43%) and placebo (49%). Thus, low-dose MR prednisone added to existing DMARD treatment produces rapid and relevant improvements in RA signs and symptoms. (Ann Rheum Dis 2013;72:204e210).
1.5. Triple DMARD induction therapy is better than MTX monotherapy in early RA The results of the tREACH study, designed to determine the most effective induction disease-modifying antirheumatic drug (DMARD) strategy in early rheumatoid arthritis (RA), and to compare one single dose of intramuscular glucocorticoids (GCs) with daily oral GCs during the induction phase have been published. The 3-month data of a single-blinded clinical trial in patients with recent-onset arthritis were used. Patients were included who had a high probability (>70%) of progressing to persistent arthritis. Patients were randomised into three induction therapy strategies: (A) combination therapy (methotrexate (MTX) þ sulfasalazine þ hydroxychloroquine) with GCs intramuscularly; (B) combination therapy with an oral GC tapering scheme and (C) MTX with oral GCs similar to B. A total of 281 patients were randomly assigned to strategy (A) (n ¼ 91), (B) (n ¼ 93) or (C) (n ¼ 97). This study found that the DAS after 3 months was lower in patients receiving initial combination therapy than in those receiving MTX monotherapy (0.39 (0.67e0.11, 95% CI)). DAS did not differ between the different GC bridging treatments. After 3 months 50% fewer biological agents were prescribed in the combination therapy groups. Thus, triple DMARD induction therapy is better than MTX monotherapy in early RA. Intramuscular and oral GCs are equally effective as bridging treatments and both can be used. (Ann Rheum Dis 2013;72:72e78).
1.6. Triple therapy is as effective as etanercept plus methotrexate in rheumatoid arthritis: the TEAR study In contrast to many previous trials of biologic agents, which have compared the combination of a biologic agent plus
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methotrexate (MTX) with placebo plus MTX, the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study correctly compared the combination of a biologic agent plus MTX with a combination of DMARDs in a double-blind trial. Apart from a small difference in total Sharp score, no differences in outcomes between the 2 treatments were reported. Similar results have been found in previous related studies. In 2005 the BeSt (Dutch acronym for BehandeleStrategiee¨n, “treatment studies”) study showed that a combination of 2 DMARDs plus an initial temporary course of glucocorticoid is as effective as infliximab plus MTX in the treatment of rheumatoid arthritis. Furthermore, in a recent meta-analysis it has been shown by means of indirect comparisons that inhibition of the radiographic progression rate was similar in 3 studies comparing 3 DMARDs with a single DMARD and 12 studies comparing the combination of a biologic agent plus MTX with a single DMARD (79% versus 84%). In the TEAR study, RA patients with symptoms <1 year were enrolled between 2002 and 2005 at 15 Swedish centres. After 3e4 months of MTX monotherapy, patients with a remaining DAS28 > 3.2 were randomised to addition of IFX or SSZ þ HCQ and followed for 21 months. Of 487 patients initially enrolled, 128 and 130 were randomised to IFX or SSZ þ HCQ, respectively. In this study, when comparing addition of IFX or SSZ þ HCQ to MTX in active early RA, no statistically significant differences in utility or QALY gain could be detected over 21 months. The etanercept plus MTX group had a borderline significantly smaller increase in total Sharp score compared with the triple therapy group (0.64 versus 1.69; P 0.047). This borderline difference is of doubtful significance. Consequently, the TEAR study, with its very strong design, is very important as it confirms the results of previous studies and adds credence to the conclusion that a combination of DMARDs is as efficient as the combination of a biologic agent plus a single DMARD, and expensive biologic agents should therefore be reserved for patients who have an inadequate response to or cannot tolerate a combination of DMARDs. (A&R 2013;65:539e542).
1.7. Head-to-head comparison of subcutaneous abatacept versus adalimumab for RA: it’s a draw! The results of the first head-to-head comparison of subcutaneous (SC) abatacept and SC adalimumab, both administered along with background methotrexate (MTX), for the treatment of RA have been published. In this 2-year study, patients with active RA who were naive to treatment with biologic agents and had an inadequate response to MTX were randomly assigned to receive 125 mg SC abatacept weekly or 40 mg SC adalimumab biweekly, both given in combination with MTX. The primary endpoint was treatment noninferiority, assessed according to the 20% improvement response (ACR20) at 1 year. At 1 year, 64.8% of patients in the SC abatacept group and 63.4% in the SC adalimumab group demonstrated an ACR20 response; the estimated difference between groups was 1.8% (95% confidence interval 5.6%, 9.2%), thus demonstrating the noninferiority of abatacept compared to adalimumab. All efficacy measures showed similar results and kinetics of response between treatments. The rate of radiographic nonprogression (defined as a total modified Sharp/van der Heijde score [SHS] less than or equal to the smallest detectable change) was 84.8% for SC
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abatacept-treated patients and 88.6% for SC adalimumabtreated patients, while the mean change from baseline in the total SHS was 0.58 and 0.38, respectively. In the SC abatacept and SC adalimumab groups, the incidence of serious adverse events (SAEs) was 10.1% and 9.1%, respectively, and the rate of serious infections was 2.2% and 2.7%, respectively. In patients treated with SC abatacept, the frequency of discontinuations due to AEs was 3.5% and discontinuations due to SAEs was 1.3%, while in patients treated with SC adalimumab, the frequencies were 6.1% and 3%, respectively. Injection site reactions occurred in 3.8% of patients receiving SC abatacept compared to 9.1% of patients receiving SC adalimumab (P ¼ 0.006). Thus, the results demonstrate that SC abatacept and SC adalimumab have comparable efficacy in patients with RA, as shown by similar kinetics of response and comparable inhibition of radiographic progression over 1 year of treatment. The safety was generally similar, other than the occurrence of significantly more local injection site reactions in patients treated with SC adalimumab. (A&R 2013;65(1):28e38).
tofacitinib 10 mg twice a day versus 24$4% for placebo. Improvements from baseline in HAQ-DI were 0$43 for 5 mg twice a day and 0$46 for 10 mg twice a day tofacitinib versus 0$18 for placebo; DAS28 < 2$6 rates were 6$7% for 5 mg twice a day tofacitinib and 8$8% for 10 mg twice a day tofacitinib versus 1$7% for placebo. The most common adverse events in months 0e3 were diarrhoea (4$9%), nasopharyngitis (4$1%), headache (4$1%), and urinary tract infection (3$0%) across tofacitinib groups, and nausea (6$8%) in the placebo group. The authors conclude that in this treatment-refractory population, tofacitinib with methotrexate had rapid and clinically meaningful improvements in signs and symptoms of RA and physical function over 6 months with manageable safety. Tofacitinib could provide an effective treatment option in patients with an inadequate response to TNFi. (Lancet 2013;381:451e60).
1.8. Methotrexate in combination with leflunomide in RA is safe and well tolerated: the SMILE study
Despite the many treatments introduced for RA, significant proportions of patients fail to achieve meaningful responses and are not adequately controlled. New therapies with novel mechanisms of action are still needed to address this unmet need. The authors of a new study postulate that direct modulation of macrophage function via granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) inhibition may provide a treatment option in RA. GM-CSF may play a central role in the pathogenesis of RA through the activation, differentiation and survival of neutrophils and macrophages. Macrophages promote synovitis via release of cytokines, chemokines, reactive oxygen and nitrogen intermediates, proteases and microparticles. The number of macrophages in synovial tissue is correlated with radiographic progression; reductions in CD68 þ macrophages correlate with improvement in disease activity scores. RA patients exhibit increased GM-CSF levels in synovial fluid, plasma and synoviocytes, and recombinant GM-CSF has been reported to exacerbate monoclonal antibody targeting the alpha subunit of GM-CSFR. In a phase 1 single ascending intravenous dose study in 32 subjects with RA, mavrilimumab showed a safety and tolerability profile supporting clinical development, and biological activity on acute phase reactants. This phase 2a study evaluated the efficacy and safety of subcutaneous (SC) mavrilimumab in subjects with moderate-to-severe active RA. This is the first study to investigate macrophage inhibition through direct blockage of GM-CSFRa as a novel therapeutic approach in RA. In this study, subcutaneous mavrilimumab (10 mg, 30 mg, 50 mg, or 100 mg) or placebo was administered every other week for 12 weeks in subjects on stable background methotrexate therapy. The primary endpoint was the proportion of subjects achieving a 1.2 decrease from baseline in DAS28CRP at week 12. Results 55.7% of mavrilimumab-treated subjects met the primary endpoint versus 34.7% placebo ( p ¼ 0.003) at week 12; for the10 mg, 30 mg, 50 mg, and 100 mg groups, responses were 41.0% ( p ¼ 0.543), 61.0% ( p ¼ 0.011), 53.8% ( p ¼ 0.071), and 66.7% ( p ¼ 0.001) respectively. Response rate differences from placebo were observed at week 2 and increased throughout the treatment period. The 100 mg dose demonstrated a significant effect versus placebo on DAS28-
The SMILE study was designed to assess the safety of treating patients with RA with a combination of methotrexate (MTX) and leflunomide (LEF) in comparison to MTX monotherapy, in clinical practice. It was a multicenter, observational, crosssectional, retrospective safety study. In total, 2975 patients were included in the study: 74% female, 26% male, mean age 62 years. Distribution of therapy: MTX monotherapy 52.2%, LEF monotherapy 7.3%, MTX plus LEF 13.9%, and neither MTX nor LEF 26.6%. Comorbid liver disease was reported in 8.1% of patients. Liver function abnormalities were reported in 12% of the MTX monotherapy group, 16% of the LEF monotherapy group, 19% of the MTX-LEF combination group, and 14% of the group not taking either drug. Neutropenia was reported in 2.3% of the MTX monotherapy group, 5.5% of the LEF monotherapy group, 3.9% of the MTX-LEF combination group, and 4.2% of the group not taking either drug. Thus, this study found that the combination of MTX and LEF was well tolerated, with adverse events comparable to those of monotherapy and the other nonbiologic disease-modifying antirheumatic drug treatment group. (J Rheumatol 2013;40:228e235).
1.9. Tofacitinib in combination with methotrexate could provide an effective treatment option in patients with active RA with an inadequate response to TNFi A study carried out to investigate the effectiveness of tofacitinib, a novel oral Janus kinase inhibitor, as a targeted immunomodulator and disease-modifying therapy for RA has been reported. This was a 6-month, double-blind, parallel-group phase 3 study in which 399 patients with moderate-to-severe RA and inadequate response to TNFi were randomly assigned in a 2:2:1:1 ratio to receive twice a day treatment with: tofacitinib 5 mg (n ¼ 133); tofacitinib 10 mg (n ¼ 134); or placebo (n ¼ 132), all with methotrexate. At month 3, patients given placebo advanced to either tofacitinib 5 mg twice a day (n ¼ 66) or 10 mg twice a day (n ¼ 66). At month 3, ACR20 response rates were 41$7% for tofacitinib 5 mg twice a day and 48$1% for
1.10. Mavrilimumab, a macrophage inhibitor acting through direct blockage of GM-CSFRa, is effective and safe in RA
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CRP < 2.6 (23.1% versus 6.7%, p ¼ 0.016), all categories of the ACR criteria (ACR20: 69.2% versus 40.0%, p ¼ 0.005; ACR50: 30.8% versus 12.0%, p ¼ 0.021; ACR70: 17.9% versus 4.0%, p ¼ 0.030), and the Health Assessment Questionnaire Disability Index (0.48 versus 0.25, p ¼ 0.005). A biomarkerbased disease activity score showed a dose-dependent decrease at week 12, indicating suppression of diseaserelated biological pathways. Adverse events were generally mild or moderate in intensity. No significant hypersensitivity reactions, serious or opportunistic infections, or changes in pulmonary parameters were observed. Thus, mavrilimumab induces rapid clinically significant responses in RA subjects, suggesting that inhibiting the mononuclear phagocyte pathway may provide a novel therapeutic approach for RA. (ARD. Online First, published on December 12, 2012).
experienced a renal relapse. Proteinuria decreased significantly (P ¼ 0.0002) from baseline to 36 months. A noteworthy histological improvement was seen in nearly all patients with a significant reduction in activity index (P ¼ 0.01). Longer depletion time and low baseline values of IgM were indicative of achieving clinical remission during the first year after treatment (P ¼ 0.03 and P ¼ 0.04, respectively). Thus, in therapy-resistant LN, BCDT induced clinical and histological improvements in the majority of patients. Transition from PR to CR was mainly seen during the second year of follow-up. Patients with longer depletion time and low baseline levels of IgM were more likely to gain a faster remission, suggesting that the clinical benefit may be linked to suppression of autoreactive plasmablasts. (Rheumatology Advance Access published January 3, 2013).
2.
2.3. Hydroxychloroquine use is associated with lower odds of persistently positive antiphospholipid antibodies and/or lupus anticoagulant in SLE
Systemic lupus erythematosus
2.1. Mannose binding lectin is a biomarker of SLE disease activity A role for mannose binding lectin (MBL) in autoimmune diseases has been demonstrated earlier and elevated level of MBL has been shown in SLE patients. In a recent study MBL has been evaluated as a potential biomarker for disease activity in SLE. In this case control study SLE patients (93 females) and 67 age, sex, ethnicity matched healthy controls were enrolled. Plasma MBL levels were quantified by ELISA. Clinical, serological and other markers of disease activity (C3, C4 and anti-dsDNA) were measured by standard laboratory procedures. The study found that the mean plasma MBL levels were significantly high in SLE patients compared to healthy controls (P < 0.0001). MBL levels were variable in different clinical categories of SLE. Lower levels were associated with musculoskeletal and cutaneous manifestations (P ¼ 0.002), while higher and intermediate MBL levels were significantly associated with nephritis in combination with other systemic manifestations (P ¼ 0.01 and P ¼ 0.04 respectively). Plasma MBL correlated with SLEDAI (P ¼ 0.0003, r ¼ 0.36), anti-dsDNA (P < 0.0001, r ¼ 0.54), proteinuria (P < 0.0001, r ¼ 0.42) and negatively correlated with C3 (P ¼ 0.007, r ¼ 0.27) and C4 (P ¼ 0.01, r ¼ 0.29). Thus, plasma MBL is a promising marker in the assessment of SLE disease activity. (Arthritis Res Ther 2012;14:R218).
2.2. Long-term follow-up in lupus nephritis patients treated with rituximab shows good clinical and histopathological response A study to investigate the long-term clinical, histological and serological affects of B-cell-depleting therapy (BCDT) in patients with LN refractory to conventional treatment has been reported. 25 patients, followed for a mean time of 36 months, were included. Renal disease activity was evaluated with the BILAG index and renal response was determined according to the LN European consensus statement. Renal biopsies were performed for histological evaluation at baseline and followup. Partial response (PR) or complete renal response (CR) was observed in 22 of 25 after a median of 12 months. Sixteen patients achieved CR after a median of 24 months. Six patients
Antiphospholipid antibodies (aPL) play an active role in the pathogenesis of the antiphos-pholipid syndrome (APS). Primary prevention in APS may be aimed at decreasing existing elevated aPL levels, or preventing high aPL titres and/or lupus anticoagulant (LAC) from developing in the first place. Hydroxychloroquine (HCQ) has been shown in retrospective studies to decrease aPL titres in laboratory studies, and to decrease thrombosis risk in patients with SLE. A recent study has investigated an association between HCQ use and persistent aPL and/or LAC in SLE. This study identified all patients over 21 years old with SLE from an urban tertiary care centre who had aPL and LAC measured on at least 2 occasions at least 12 weeks apart. It defined the presence of persistent LACþ and/or at least 1 aPL 40 U [immunoglobulin A (IgA), IgG, or IgM] as the main outcome variable. Among 90 patients included in the study, 17 (19%) had persistent LACþ and/or at least 1 aPL 40 U. HCQ use was associated with significantly lower odds of having persistent LACþ and/or aPL 40 U (OR 0.21, 95% CI 0.05, 0.79, p ¼ 0.02), adjusted for age, ethnicity, and sex. This is the first study to show that HCQ use is associated with lower odds of having persistently positive LAC and/or aPL. (J Rheumatol 2013;40:30e33).
2.4. Vitamin D supplementation is recommended in patients with SLE Vitamin D has potent immunomodulatory properties that support its use in the treatment of autoimmune conditions, including SLE. A recent study assessed vitamin D status in patients with SLE and determined alterations in inflammatory and haemostatic markers and disease activity before and after vitamin D supplementation. 267 SLE patients were randomized 2:1 to receive either oral cholecalciferol 2000 IU/day or placebo for 12 months. Vitamin D levels were measured by Liaison immunoassay (normal 30e100 ng/ml). Serum levels between 10 and 30 ng/ml were classified as vitamin D insufficiency and levels < 10 ng/ml as vitamin D deficiency. The mean 25(OH)D level at baseline was 19.8 ng/ml in patients compared to 28.7 ng/ml in controls. The overall prevalence of suboptimal and deficient 25(OH)D serum levels among patients with SLE at
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baseline was 69% and 39%, respectively. Lower 25(OH)D levels correlated significantly with higher SLE disease activity. At 12 months of therapy, there was a significant improvement in levels of inflammatory and haemostatic markers as well as disease activity in the treatment group compared to the placebo group. Thus, this study concluded that Vitamin D supplementation in patients with SLE is recommended because increased vitamin D levels seem to ameliorate inflammatory and hemostatic markers and show a tendency towards subsequent clinical improvement. (J Rheumatol 2013;40:265e272).
WOMAC score were used to evaluate the efficacy of hyaluronic acid injections before and 3 and 6 months after treatment. Both treatment regimens resulted in a significant improvement versus baseline in all endpoints at 3 and 6 months ( p less than 0.001). Treatment with Variofill resulted in a high percentage improvement in Visual Analogue Scale pain, WOMAC score pain and physical activity, when compared to Synvisc viscosupplementation, at 6 months ( p less than 0.05). These results are encouraging for larger clinical trials with Variofill in larger cohorts of patients affected by osteoarthritis of the knee. (Int J Immunopathol Pharmacol. 2012;25:1093e1098).
3.
3.3. Strontium ranelate could be the first structure modifying drug for treatment of knee osteoarthritis
Osteoarthritis
3.1. Idiopathic hand osteoarthritis and haemochromatosis arthropathy differ significantly Haemochromatosis arthropathy is a secondary OA and the most frequent and earliest clinical presentation of hereditary haemochromatosis (HH). The aim of a recent study was to perform a direct clinical, functional and radiographic comparison with idiopathic hand OA (HOA) to unravel important differences between these clinical entities. In total, 299 patients (141 with HH arthropathy of the hands and 158 patients with idiopathic HOA) were recruited. It was seen that HH arthropathy and HOA differed significantly: patients with HH arthropathy were younger and predominantly male as compared with HOA. In males but not females, HH arthropathy led to an earlier start of symptoms than in HOA. Patients with HOA had more tender joints and worse hand function than patients with HH arthropathy, although subjective measures of joint pain and function were similar. MCP and wrist joint involvement was more frequent and severe in HH arthropathy, while HOA patients more frequently had degenerative changes in the first CMC as well as PIP and DIP joints. Thus, HH arthropathy and idiopathic HOA differ significantly in terms of epidemiology, localization, severity of symptoms and radiographic changes. (Rheumatology. Advance Access published January 12, 2013).
3.2. Viscosupplementation with a new highly crosslinked hyaluronic acid may be better than that with the widely used Synvisc in knee OA Osteoarthritis is characterized by progressive articular cartilage degeneration, changes in subchondral bone and synovial inflammation, leading to pain and disability. Viscosupplementation with hyaluronic acid has been widely investigated due to the viscoelastic properties of this compound to manage pain improving the ability to perform daily activities in patients affected by osteoarthritis. A recent study has investigated the clinical effectiveness of viscosupplementation with a new highly cross-linked hyaluronic acid, Variofill, in patients affected by bilateral knee osteoarthritis in comparison with the widely used Synvisc. A total of 20 patients, aged between 24 and 74 years and affected by bilateral knee osteoarthritis, participated in this pilot randomized triple-blind clinical study. They received two injections (2 ml each) of Synvisc in their left knee and 2 injections (2 ml each) of Variofill in their right knee spaced 15 days apart. Visual Analogue Scale and
Background strontium ranelate is currently used for osteoporosis. The international, double-blind, randomised, placebo-controlled Strontium ranelate Efficacy in Knee Osteoarthritis trial evaluated its effect on radiological progression of knee osteoarthritis. Patients with knee osteoarthritis (OA) (Kellgren and Lawrence grade 2 or 3, and joint space width (JSW) 2.5e5 mm) were randomly allocated to strontium ranelate 1 g/day (n ¼ 558), 2 g/day (n ¼ 566) or placebo (n ¼ 559). The primary endpoint was radiographical change in JSW (medial tibiofemoral compartment) over 3 years versus placebo. Secondary endpoints included radiological progression, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and knee pain. The intention-to-treat population included 1371 patients. Treatment with strontium ranelate was associated with smaller degradations in JSW than placebo (1 g/day: 0.23 (SD 0.56) mm; 2 g/day: 0.27 (SD 0.63) mm; placebo: 0.37 (SD 0.59) mm); treatmentplacebo differences were 0.14 (SE 0.04), 95% CI 0.05e0.23, p < 0.001 for 1 g/day and 0.10 (SE 0.04), 95% CI 0.02e0.19, p ¼ 0.018 for 2 g/day. Fewer radiological progressors were observed with strontium ranelate ( p < 0.001 and p ¼ 0.012 for 1 and 2 g/day). There were greater reductions in total WOMAC score ( p ¼ 0.045), pain subscore ( p ¼ 0.028), physical function subscore ( p ¼ 0.099) and knee pain ( p ¼ 0.065) with strontium ranelate 2 g/day. Strontium ranelate was well tolerated. Thus, treatment with strontium ranelate 1 and 2 g/day is associated with a significant effect on structure in patients with knee OA, and a beneficial effect on symptoms for strontium ranelate 2 g/day. (Ann Rheum Dis 2013;72:179e186).
3.4.
Methotrexate for pain relief in knee osteoarthritis?
Synovitis is very common in knee OA and associated with pain. An open-label study has evaluated an anti-synovitis therapy, MTX, for pain relief in knee OA. Inclusion criteria included pain visual analogue scale (VAS) > 40/100 mm, ACR clinical criteria for knee OA and intolerance/inefficacy of NSAID and opioids. US at baseline and 24 weeks assessed effusion and synovial thickness. Patients received MTX up to 20 mg/week for 24 weeks. 30 participants were recruited; mean age 64.5 years, median pain VAS 68 mm. At 24 weeks, 43% achieved 30% reduction in pain VAS, 23% achieved 50% reduction and 13% had worsened. 13 OARSI responder criteria. All had effusion/ synovitis at baseline. There was no correlation between change in imaging and change in pain scores at 24 weeks. This
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open-label trial suggests analgesic efficacy for MTX in OA knee and recommends that a randomized controlled trial is warranted. (Rheumatology. 2013 Jan 7 [Epub ahead of print]).
4.
Complex regional pain syndrome
4.1. In patients with CRPS-I, four i.v. infusions of neridronate 100 mg are associated with clinically relevant and persistent benefits Complex regional pain syndrome type I (CRPS-I) is a severely disabling pain syndrome for which no definite treatment has been established. The aim of a recent multi-centre, randomized, double-blind placebo-controlled trial was to test the efficacy of the amino-bisphosphonate neridronate in patients with CRP-I. 82 patients with CRP-I at either hand or foot were randomly assigned to i.v. infusion of 100 mg neridronate given four times over 10 days or placebo. After 50 days the former placebo patients were given open-label the same regimen of neridronate. Within the first 20 days, visual analogue scale (VAS) score decreased significantly more in the neridronate group. In the following 20 days, VAS remained unchanged in the placebo group and further decreased in the active group by 46.5 mm versus 22.6 mm for placebo group (P < 0.0001). Significant improvements versus placebo were observed also for a number of other indices of pain and quality of life. During the open-extension phase in the formerly placebo group the results of treatment were superimposable on those seen during the blind phase in the active group. A year later none of the patients had symptoms linked to CRPS-I. Thus, in patients with acute CRPS-I, four i.v. infusions of neridronate 100 mg are associated with clinically relevant and persistent benefits. These results provide conclusive evidence that the use of bisphosphonates, at appropriate doses, is the treatment of choice for CRPS-I. (Rheumatology 2013;52:534e542).
5.
NSAIDs
5.1. Triple therapy combination of diuretics with angiotensin converting enzyme inhibitors or angiotensin receptor blockers and NSAIDs is associated with an increased risk of acute kidney injury A study has assessed whether or not a double therapy combination consisting of diuretics, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers with addition of NSAIDs and the triple therapy combination of two of the aforementioned antihypertensive drugs to which NSAIDs are added are associated with an increased risk of acute kidney injury. A cohort of 487,372 users of antihypertensive drugs participated in this study. The main outcome measures were rate ratios with 95% confidence intervals of acute kidney injury associated with current use of double and triple therapy combinations of antihypertensive drugs with NSAIDs. During a mean follow-up of 5.9 years, 2215 cases of acute kidney injury were identified (incidence rate 7/10,000 person years). Overall, current use of a double therapy combination containing either diuretics or angiotensin converting enzyme inhibitors or
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angiotensin receptor blockers with NSAIDs was not associated with an increased rate of acute kidney injury. In contrast, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio 1.31, 95% confidence interval 1.12e1.53). In secondary analyses, the highest risk was observed in the first 30 days of use (rate ratio 1.82, 1.35e2.46). Thus, a triple therapy combination consisting of diuretics with angiotensin converting enzyme inhibitors or angiotensin receptor blockers and NSAIDs was associated with an increased risk of acute kidney injury. The risk was greatest at the start of treatment. Although antihypertensive drugs have cardiovascular benefits, vigilance may be warranted when they are used concurrently with NSAIDs. (BMJ 2013;346:e8525).
6.
Juvenile idiopathic arthritis
6.1. Ultrasound-detected synovial abnormalities are frequent in clinically inactive JIA, but do not predict a flare of synovitis To investigate whether children with JIA in clinical remission have subclinical synovial disease on ultrasound, and whether ultrasound abnormalities predict an early flare of synovitis, 39 consecutive children who had clinically defined inactive disease (ID) for a minimum of3 months underwent ultrasound assessment of 52 joints. All joints were scanned for synovial hyperplasia, joint effusion, power Doppler (PD) signal and tenosynovitis. Patients were then followed clinically for up to 2 years until a flare of synovitis occurred in one or more joints or until the 2-year visit if the disease remained in clinical remission. It was found that synovial hyperplasia, joint effusion, PD signal and tenosynovitis in at least one joint were detected in 76.9%, 66.7%, 33.3% and 15.4% of patients, respectively. During the 2-year follow-up, 24 patients (61.5%) experienced sustained ID, whereas 15 patients (38.5%) had a flare of synovitis in a total of 45 joints after a median of 10.6 months (range 6.3e13.7 months). At study entry, the rate of synovial hyperplasia, joint effusion and tenosynovitis was comparable between patients with persistent ID and patients with synovitis flare, whereas patients with persistent ID had a greater frequency of PD signal than patients with synovitis flare. Only 17 of the 45 flared joints had ultrasound abnormalities at study entry. Thus, this study found that ultrasound-detected synovial abnormalities are common in children with JIA in clinical remission. However, the presence of ultrasound pathology does not predict an early flare of synovitis in the affected joints. (Ann Rheum Dis 2013;72:223e228).
7.
Ankylosing spondylitis
7.1. Early inflammatory lesions may resolve without new bone formation in ankylosing spondylitis: a window of opportunity Although MRI data supports a link between spinal inflammation and formation of new bone in ankylosing spondylitis, anti-TNFa therapies have not been shown to prevent new bone formation. A new study aimed to demonstrate that while
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acute lesions resolve completely, more advanced lesions, characterised by evidence of reparation, are associated with new bone formation. In this study, MRI scans were performed at baseline, 12 and 52 weeks in 76 ankylosing spondylitis patients recruited to a placebo-controlled trial of adalimumab therapy. New syndesmophytes were assessed on lateral radiographs of the cervical and lumbar spine at baseline and 104 weeks. Anonymised MRI scans were read independently by two readers who recorded the presence/absence of acute (type A) and advanced (type B) vertebral corner inflammatory lesions (CIL) and fat lesions. New syndesmophytes developed significantly more frequently from type B CIL (16.7%) compared with type A CIL (2.9%) ( p ¼ 0.002) or no CIL (2.5%) ( p < 0.0001). This was also observed for both baseline and new vertebral corner fat lesions evolving over 52 weeks (11.1% ( p < 0.001) and 6.8% ( p ¼ 0.03), respectively). The association with type B CIL and fat was significant after adjustment for the extent of syndesmophytes/ankylosis at baseline. The data supports the hypothesis that new bone formation is more likely in advanced inflammatory lesions and proceeds through a process of fat metaplasia, supporting a window of opportunity for disease modification. Early inflammatory lesions may resolve without sequelae, while resolution of inflammation in more advanced inflammatory lesions, where reparative changes are already evident, is accompanied by new bone formation. (Ann Rheum Dis 2013;72:23e28).
8.
Inflammatory myopathy
antisynthetase syndrome with corticosteroid-refractory interstitial lung disease (ILD). Prednisone was the first-line treatment in all cases (1 mg/kg/ day orally, then tapering after 1 year). Patients with corticosteroid-refractory or relapsing ILD were then included in this retrospective study. All patients started CYC (3 mg/kg/ day) without increasing prednisone dosage. Both PFT and chest HRCT were regularly reassessed during follow-up. 18 patients with antisynthetase syndrome were evaluated; 17 had ILD (13 women; median age at ILD onset 57 yrs); all patients failed prednisone within 12 months of ILD onset and subsequently started CYC. The median follow-up on CYC was 96 months. Upon starting CYC, median forced vital capacity (FVC) was 60%, median DLCO 60%, and median Kazerooni score for ILD by HRCT chest16 (IQR 7e18). After 1 year of CYC, FVC ( p ¼ 0.0006), DLCO ( p ¼ 0.0010), and total Kazerooni score ( p ¼ 0.0002) improved and prednisone was tapered (median reduced from 25 mg/day to 2.5 mg/day; p < 0.0001). The results were substantially maintained including at last available follow-up. CYC side effects were hypertension (5 patients) and creatinine increase (6 patients). CYC was reduced in 3 cases and withdrawn in 4. Three out of 4 patients who interrupted CYC experienced ILD relapse; 2 patients recommenced lowdose CYC with subsequent ILD control. One patient refused re-treatment and subsequently died. The authors of this study conclude that CYC is effective and substantially safe in patients with anti-Jo1 antisynthetase syndrome with corticosteroid-refractory ILD. CYC withdrawal may be associated with ILD relapse, and low-dose CYC is effective in ILD control. (J Rheumatol First Release Feb 15 2013).
8.1. Patients with idiopathic inflammatory myopathies have low serum levels of vitamin D
9. In a study designed to compare serum levels of 25(OH) vitamin D in patients with idiopathic inflammatory myopathies (IIM) (polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM) and juvenile DM (JDM)) with healthy controls, serum samples from 149 patients with IIM and 290 healthy controls were analysed for 25(OH) vitamin D. Patients with IIM had significantly lower serum levels of 25(OH) vitamin D than healthy controls (median 39 (10e168) nmol/l versus 68 (19e197) nmol/l; p ¼ 0.0001). There was no significant difference in vitamin D levels between the myositis subgroups. When vitamin D levels were subclassified into deficient (<50 nmol/l), insufficient (50e74 nmol/l) and normal (75 nmol/l),most of the patients with PM (68%), DM (65%) and IBM (53%) had deficient levels compared with only 60 (21%) healthy individuals. In patients with IIM the OR for deficient versus normal was 17.7 and the OR for insufficient versus normal was 2.4. Thus, low serum levels of vitamin D were found in most patients with IIM and may confer a risk factor for developing adult myositis, similar to some other autoimmune diseases. (Ann Rheum Dis 2013;72:512e516).
8.2. Cyclosporine is effective and safe in anti-Jo1positive patients with corticosteroid-refractory interstitial lung disease A study has described the long-term effectiveness and safety of cyclosporine (CYC) in patients with anti-Jo1-positive
ANA testing
9.1. More than 90% of patients referred to a rheumatology clinic for a positive ANA test result have no evidence for an ANA-associated rheumatic disease A retrospective study investigated the clinical utility of a positive ANA test performed outside of the rheumatology setting. Prior studies have investigated the frequency of ANA positivity within the general population. The purpose of this investigation was to evaluate the clinical utility of a positive ANA test result in a real-world setting by reviewing the final diagnoses of patients who were referred to a tertiary rheumatology clinic for evaluation of a positive ANA test result. A total of 232 patients were referred for a positive ANA test result. The positive predictive value of a positive ANA test result in this cohort was 2.1% for lupus and 9.1% for any ANAassociated rheumatic disease. No ANA-associated rheumatic disease was identified in patients with an ANA < 1:160. The most common reason for ordering ANA testing was widespread pain and tenderness (23.2%). Thus, in this retrospective study, more than 90% of patients who were referred to a tertiary rheumatology clinic for a positive ANA test result had no evidence for an ANA-associated rheumatic disease. The poor predictive value of a positive ANA in this cohort was largely attributable to unnecessary testing in patients with low pretest probabilities for ANA-associated rheumatic disease. (Am J Med 2013;126:342e348).
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10.
Patient-reported outcome measures
10.1. Patients completing patient-reported outcome measures may not be able to understand what they are answering and may be unable to give an accurate perspective on their condition A study to assess the reading levels required to complete 10 patient-reported outcome measures (PROs) commonly used in rheumatology clinical and research settings has been reported. Four reviewers critiqued each measure blindly using two standardized readability indexes and a final readability score for each PRO was agreed. Only six of the PROs met the
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recommended reading level for health education literature. Thus, many people completing PROs will not be able to understand what they are answering and will be unable to give an accurate perspective on their condition. PROs in rheumatology should avoid using complicated words so that patients can understand and provide valid responses. (Rheumatology 2013;52:460e464).
Conflicts of interest The author has none to declare.
Answers to Rheumatology Quiz
1a*, 2b**, 3c***, 4cy, 5byy, 6cyyy, 7dx, 8bxx, 9dxxx, 10d{
* In 1930, Benediktos Adamantiades, a Greek ophthalmologist described “A case of relapsing iritis with hypopyon” in a 20-year old man with the three cardinal signs of the disease e genital ulcers, arthritis, and the ocular signs. In 1937, Hulusi Behcet, a dermatologist from Turkey described three patients with oral and genital ulcerations and hypopyon uveitis. ** Although anterior uveitis was described in the initial patients, posterior uveitis is the hallmark lesion of BD. *** Acneiform nodules in BD can be present over any part of the body; they may not always be hair follicle associated; skin biopsy in BD lesions shows an inflammatory infiltrate. y Brain. 1999;122:2183e2194. yy Named after two British physicians, John Patterson Hughes and Peter George Ingle Stovin, who first described it in 1959. Presents with fever and hemoptysis. yyy Pulmonary embolism is uncommon in BD; arterial aneurysms are superficial “arterial aphthae”. x All the other lesions have also been reported in BD. xx Erythematous papule or pustule formation at a skin site 24e48 h following insertion of a needle into the skin. xxx MAGIC ¼ mouth and genital ulcerations with inflamed cartilage has features of both BD and RP. { Non-erosive, non-deforming oligoarthritis which responds well to colchicine. Azathioprine and TNF inhibitors are used for refractory arthritis.
Available online at www.indianjrheumatol.com and www.sciencedirect.com
Rheumatology Reviews
Rheumatology reviews: JanuaryeMarch 2013 Sukhbir Uppal Department of Medicine, University Hospital Sharjah, United Arab Emirates
1.
Rheumatoid arthritis
1.1. Methotrexate use is associated with a 70% reduction in mortality in RA A study to examine the relationship between methotrexate (MTX) use and mortality in RA has been published. This study examined 5626 RA patients prospectively for 25 years to determine the risk of death associated with MTX use. During follow-up, 666 patients (12%) died. MTX use was associated with reduced risk of death (adjusted hazard ratio 0.30). Selective MTX cessation immediately before death did not account for the protective association of MTX use with mortality. Only MTX use for >1 year was associated with lower risks of mortality, but associations were not stronger with longer durations of use. Thus, MTX use is associated with a 70% reduction in mortality in RA (A&R 2013;65:334e342).
1.2. Glucocorticoids are associated with an increased risk of myocardial infarction in RA A study has assessed the effect of glucocorticoids (GCs) on acute myocardial infarction (MI) risk in patients with RA. Using administrative health data, the authors conducted a population-based cohort study of 8384 incident RA cases (1997e2006). Primary exposure was incident GC use. MI events were ascertained using hospitalization and vital statistics data. GC use was modelled as four alternative timedependent variables (current use, current dose, cumulative dose and cumulative duration), adjusting for demographics, comorbidities, cardiovascular drug use, propensity score and RA characteristics. Sensitivity analyses explored potential effects of unmeasured confounding. Within 50,238 person years in 8384 RA cases, 298 incident MI events were identified. Multivariable models showed that current GC use was associated with 68% increased risk of MI [HR ¼ 1.68]. Similarly, separate multivariable models showed that current daily dose (HR ¼ 1.14 per each 5 mg/day increase), cumulative duration
of use (HR ¼ 1.14 per year of GC use) and total cumulative dose (HR ¼ 1.06 per gram accumulated in the past) were also associated with increased risk of MI. Furthermore, in the same multivariable model, current dose and cumulative use were independently associated with an increased risk of MI (10% per additional year on GCs and 13% per 5 mg/day increase). Thus, GCs are associated with an increased risk of MI in RA. The results suggest a dual effect of GCs on MI risk, an immediate effect mediated through current dosage and a long-term effect of cumulative exposure. (Rheumatology 2013;52:68e75).
1.3. DAS28-CRP assessed with 3 and 4 variables in patients with RA should not be used interchangeably in the daily clinic without caution The DAS28-CRP(4) composite measure for RA is based on 4 variables: tender and swollen joint counts, CRP, and patient global assessment. DAS28-CRP(3) includes only 3 variables, because patient global assessment has been omitted. Thresholds for low and high disease activity are the same for the 2 scores. A recent study comparing the 2 DAS scores and their responses on the individual patient level has been reported. Baseline and 12-week disease activity data from 239 patients with RA treated with a biological agent were extracted. Baseline values for DAS28-CRP(4) and DAS28-CRP(3) were 4.8 1.2 and 4.6 1.1, respectively. At 12 weeks, DAS28-CRP(4) had improved by 1.39 1.34 ( p < 0.0001). At that timepoint the bias of DAS28-CRP(3) was 0.07. The bias of the DAS28CRP(3) response was þ0.21. Effect size for DAS28-CRP(4) was 1.2 1.1 versus 1.1 1.1 for DAS28-CRP(3) ( p < 0.0001). Compared to DAS28-CRP(4), DAS28-CRP(3) categorized 33% fewer patients as having a high level of disease activity, 8% fewer patients as good responders, and 12% more patients as nonresponders. Thus, mean values of DAS28-CRP(4) and DAS28-CRP(3) agree well, but in the individual patient the difference between the scores and their responses may be substantial. (J Rheumatol First Release March 1 2013).
E-mail address: [email protected]. 0973-3698/$ e see front matter Copyright ª 2013, Indian Rheumatology Association. All rights reserved. http://dx.doi.org/10.1016/j.injr.2013.04.007
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1.4. Evening low-dose modified release prednisone added to existing DMARD treatment produces rapid and relevant improvements in RA signs and symptoms In order to assess the efficacy and safety of low-dose prednisone chronotherapy using a new modified-release (MR) formulation for the treatment of RA, this 12-week, doubleblind, placebo-controlled study randomized patients with active RA (n ¼ 350) 2:1 to receive MR prednisone 5 mg or placebo once daily in the evening in addition to their existing DMARD treatment. It was found that MR prednisone plus DMARD treatment produced higher response rates for ACR20 (48% versus 29%, p < 0.001) and ACR50 (22% versus 10%, p < 0.006) and a greater median relative reduction from baseline in morning stiffness (55% versus 35%, p < 0.002) at week 12 than placebo plus DMARD treatment. Significantly greater reductions in severity of RA (Disease Activity Score 28) ( p < 0.001) and fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue score) ( p ¼ 0.003) as well as a greater improvement in physical function (36-item Short- Form Health Survey score) ( p < 0.001) were seen at week 12 for MR prednisone versus placebo. The incidence of adverse events was similar for MR prednisone (43%) and placebo (49%). Thus, low-dose MR prednisone added to existing DMARD treatment produces rapid and relevant improvements in RA signs and symptoms. (Ann Rheum Dis 2013;72:204e210).
1.5. Triple DMARD induction therapy is better than MTX monotherapy in early RA The results of the tREACH study, designed to determine the most effective induction disease-modifying antirheumatic drug (DMARD) strategy in early rheumatoid arthritis (RA), and to compare one single dose of intramuscular glucocorticoids (GCs) with daily oral GCs during the induction phase have been published. The 3-month data of a single-blinded clinical trial in patients with recent-onset arthritis were used. Patients were included who had a high probability (>70%) of progressing to persistent arthritis. Patients were randomised into three induction therapy strategies: (A) combination therapy (methotrexate (MTX) þ sulfasalazine þ hydroxychloroquine) with GCs intramuscularly; (B) combination therapy with an oral GC tapering scheme and (C) MTX with oral GCs similar to B. A total of 281 patients were randomly assigned to strategy (A) (n ¼ 91), (B) (n ¼ 93) or (C) (n ¼ 97). This study found that the DAS after 3 months was lower in patients receiving initial combination therapy than in those receiving MTX monotherapy (0.39 (0.67e0.11, 95% CI)). DAS did not differ between the different GC bridging treatments. After 3 months 50% fewer biological agents were prescribed in the combination therapy groups. Thus, triple DMARD induction therapy is better than MTX monotherapy in early RA. Intramuscular and oral GCs are equally effective as bridging treatments and both can be used. (Ann Rheum Dis 2013;72:72e78).
1.6. Triple therapy is as effective as etanercept plus methotrexate in rheumatoid arthritis: the TEAR study In contrast to many previous trials of biologic agents, which have compared the combination of a biologic agent plus
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methotrexate (MTX) with placebo plus MTX, the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study correctly compared the combination of a biologic agent plus MTX with a combination of DMARDs in a double-blind trial. Apart from a small difference in total Sharp score, no differences in outcomes between the 2 treatments were reported. Similar results have been found in previous related studies. In 2005 the BeSt (Dutch acronym for BehandeleStrategiee¨n, “treatment studies”) study showed that a combination of 2 DMARDs plus an initial temporary course of glucocorticoid is as effective as infliximab plus MTX in the treatment of rheumatoid arthritis. Furthermore, in a recent meta-analysis it has been shown by means of indirect comparisons that inhibition of the radiographic progression rate was similar in 3 studies comparing 3 DMARDs with a single DMARD and 12 studies comparing the combination of a biologic agent plus MTX with a single DMARD (79% versus 84%). In the TEAR study, RA patients with symptoms <1 year were enrolled between 2002 and 2005 at 15 Swedish centres. After 3e4 months of MTX monotherapy, patients with a remaining DAS28 > 3.2 were randomised to addition of IFX or SSZ þ HCQ and followed for 21 months. Of 487 patients initially enrolled, 128 and 130 were randomised to IFX or SSZ þ HCQ, respectively. In this study, when comparing addition of IFX or SSZ þ HCQ to MTX in active early RA, no statistically significant differences in utility or QALY gain could be detected over 21 months. The etanercept plus MTX group had a borderline significantly smaller increase in total Sharp score compared with the triple therapy group (0.64 versus 1.69; P 0.047). This borderline difference is of doubtful significance. Consequently, the TEAR study, with its very strong design, is very important as it confirms the results of previous studies and adds credence to the conclusion that a combination of DMARDs is as efficient as the combination of a biologic agent plus a single DMARD, and expensive biologic agents should therefore be reserved for patients who have an inadequate response to or cannot tolerate a combination of DMARDs. (A&R 2013;65:539e542).
1.7. Head-to-head comparison of subcutaneous abatacept versus adalimumab for RA: it’s a draw! The results of the first head-to-head comparison of subcutaneous (SC) abatacept and SC adalimumab, both administered along with background methotrexate (MTX), for the treatment of RA have been published. In this 2-year study, patients with active RA who were naive to treatment with biologic agents and had an inadequate response to MTX were randomly assigned to receive 125 mg SC abatacept weekly or 40 mg SC adalimumab biweekly, both given in combination with MTX. The primary endpoint was treatment noninferiority, assessed according to the 20% improvement response (ACR20) at 1 year. At 1 year, 64.8% of patients in the SC abatacept group and 63.4% in the SC adalimumab group demonstrated an ACR20 response; the estimated difference between groups was 1.8% (95% confidence interval 5.6%, 9.2%), thus demonstrating the noninferiority of abatacept compared to adalimumab. All efficacy measures showed similar results and kinetics of response between treatments. The rate of radiographic nonprogression (defined as a total modified Sharp/van der Heijde score [SHS] less than or equal to the smallest detectable change) was 84.8% for SC
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abatacept-treated patients and 88.6% for SC adalimumabtreated patients, while the mean change from baseline in the total SHS was 0.58 and 0.38, respectively. In the SC abatacept and SC adalimumab groups, the incidence of serious adverse events (SAEs) was 10.1% and 9.1%, respectively, and the rate of serious infections was 2.2% and 2.7%, respectively. In patients treated with SC abatacept, the frequency of discontinuations due to AEs was 3.5% and discontinuations due to SAEs was 1.3%, while in patients treated with SC adalimumab, the frequencies were 6.1% and 3%, respectively. Injection site reactions occurred in 3.8% of patients receiving SC abatacept compared to 9.1% of patients receiving SC adalimumab (P ¼ 0.006). Thus, the results demonstrate that SC abatacept and SC adalimumab have comparable efficacy in patients with RA, as shown by similar kinetics of response and comparable inhibition of radiographic progression over 1 year of treatment. The safety was generally similar, other than the occurrence of significantly more local injection site reactions in patients treated with SC adalimumab. (A&R 2013;65(1):28e38).
tofacitinib 10 mg twice a day versus 24$4% for placebo. Improvements from baseline in HAQ-DI were 0$43 for 5 mg twice a day and 0$46 for 10 mg twice a day tofacitinib versus 0$18 for placebo; DAS28 < 2$6 rates were 6$7% for 5 mg twice a day tofacitinib and 8$8% for 10 mg twice a day tofacitinib versus 1$7% for placebo. The most common adverse events in months 0e3 were diarrhoea (4$9%), nasopharyngitis (4$1%), headache (4$1%), and urinary tract infection (3$0%) across tofacitinib groups, and nausea (6$8%) in the placebo group. The authors conclude that in this treatment-refractory population, tofacitinib with methotrexate had rapid and clinically meaningful improvements in signs and symptoms of RA and physical function over 6 months with manageable safety. Tofacitinib could provide an effective treatment option in patients with an inadequate response to TNFi. (Lancet 2013;381:451e60).
1.8. Methotrexate in combination with leflunomide in RA is safe and well tolerated: the SMILE study
Despite the many treatments introduced for RA, significant proportions of patients fail to achieve meaningful responses and are not adequately controlled. New therapies with novel mechanisms of action are still needed to address this unmet need. The authors of a new study postulate that direct modulation of macrophage function via granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) inhibition may provide a treatment option in RA. GM-CSF may play a central role in the pathogenesis of RA through the activation, differentiation and survival of neutrophils and macrophages. Macrophages promote synovitis via release of cytokines, chemokines, reactive oxygen and nitrogen intermediates, proteases and microparticles. The number of macrophages in synovial tissue is correlated with radiographic progression; reductions in CD68 þ macrophages correlate with improvement in disease activity scores. RA patients exhibit increased GM-CSF levels in synovial fluid, plasma and synoviocytes, and recombinant GM-CSF has been reported to exacerbate monoclonal antibody targeting the alpha subunit of GM-CSFR. In a phase 1 single ascending intravenous dose study in 32 subjects with RA, mavrilimumab showed a safety and tolerability profile supporting clinical development, and biological activity on acute phase reactants. This phase 2a study evaluated the efficacy and safety of subcutaneous (SC) mavrilimumab in subjects with moderate-to-severe active RA. This is the first study to investigate macrophage inhibition through direct blockage of GM-CSFRa as a novel therapeutic approach in RA. In this study, subcutaneous mavrilimumab (10 mg, 30 mg, 50 mg, or 100 mg) or placebo was administered every other week for 12 weeks in subjects on stable background methotrexate therapy. The primary endpoint was the proportion of subjects achieving a 1.2 decrease from baseline in DAS28CRP at week 12. Results 55.7% of mavrilimumab-treated subjects met the primary endpoint versus 34.7% placebo ( p ¼ 0.003) at week 12; for the10 mg, 30 mg, 50 mg, and 100 mg groups, responses were 41.0% ( p ¼ 0.543), 61.0% ( p ¼ 0.011), 53.8% ( p ¼ 0.071), and 66.7% ( p ¼ 0.001) respectively. Response rate differences from placebo were observed at week 2 and increased throughout the treatment period. The 100 mg dose demonstrated a significant effect versus placebo on DAS28-
The SMILE study was designed to assess the safety of treating patients with RA with a combination of methotrexate (MTX) and leflunomide (LEF) in comparison to MTX monotherapy, in clinical practice. It was a multicenter, observational, crosssectional, retrospective safety study. In total, 2975 patients were included in the study: 74% female, 26% male, mean age 62 years. Distribution of therapy: MTX monotherapy 52.2%, LEF monotherapy 7.3%, MTX plus LEF 13.9%, and neither MTX nor LEF 26.6%. Comorbid liver disease was reported in 8.1% of patients. Liver function abnormalities were reported in 12% of the MTX monotherapy group, 16% of the LEF monotherapy group, 19% of the MTX-LEF combination group, and 14% of the group not taking either drug. Neutropenia was reported in 2.3% of the MTX monotherapy group, 5.5% of the LEF monotherapy group, 3.9% of the MTX-LEF combination group, and 4.2% of the group not taking either drug. Thus, this study found that the combination of MTX and LEF was well tolerated, with adverse events comparable to those of monotherapy and the other nonbiologic disease-modifying antirheumatic drug treatment group. (J Rheumatol 2013;40:228e235).
1.9. Tofacitinib in combination with methotrexate could provide an effective treatment option in patients with active RA with an inadequate response to TNFi A study carried out to investigate the effectiveness of tofacitinib, a novel oral Janus kinase inhibitor, as a targeted immunomodulator and disease-modifying therapy for RA has been reported. This was a 6-month, double-blind, parallel-group phase 3 study in which 399 patients with moderate-to-severe RA and inadequate response to TNFi were randomly assigned in a 2:2:1:1 ratio to receive twice a day treatment with: tofacitinib 5 mg (n ¼ 133); tofacitinib 10 mg (n ¼ 134); or placebo (n ¼ 132), all with methotrexate. At month 3, patients given placebo advanced to either tofacitinib 5 mg twice a day (n ¼ 66) or 10 mg twice a day (n ¼ 66). At month 3, ACR20 response rates were 41$7% for tofacitinib 5 mg twice a day and 48$1% for
1.10. Mavrilimumab, a macrophage inhibitor acting through direct blockage of GM-CSFRa, is effective and safe in RA
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CRP < 2.6 (23.1% versus 6.7%, p ¼ 0.016), all categories of the ACR criteria (ACR20: 69.2% versus 40.0%, p ¼ 0.005; ACR50: 30.8% versus 12.0%, p ¼ 0.021; ACR70: 17.9% versus 4.0%, p ¼ 0.030), and the Health Assessment Questionnaire Disability Index (0.48 versus 0.25, p ¼ 0.005). A biomarkerbased disease activity score showed a dose-dependent decrease at week 12, indicating suppression of diseaserelated biological pathways. Adverse events were generally mild or moderate in intensity. No significant hypersensitivity reactions, serious or opportunistic infections, or changes in pulmonary parameters were observed. Thus, mavrilimumab induces rapid clinically significant responses in RA subjects, suggesting that inhibiting the mononuclear phagocyte pathway may provide a novel therapeutic approach for RA. (ARD. Online First, published on December 12, 2012).
experienced a renal relapse. Proteinuria decreased significantly (P ¼ 0.0002) from baseline to 36 months. A noteworthy histological improvement was seen in nearly all patients with a significant reduction in activity index (P ¼ 0.01). Longer depletion time and low baseline values of IgM were indicative of achieving clinical remission during the first year after treatment (P ¼ 0.03 and P ¼ 0.04, respectively). Thus, in therapy-resistant LN, BCDT induced clinical and histological improvements in the majority of patients. Transition from PR to CR was mainly seen during the second year of follow-up. Patients with longer depletion time and low baseline levels of IgM were more likely to gain a faster remission, suggesting that the clinical benefit may be linked to suppression of autoreactive plasmablasts. (Rheumatology Advance Access published January 3, 2013).
2.
2.3. Hydroxychloroquine use is associated with lower odds of persistently positive antiphospholipid antibodies and/or lupus anticoagulant in SLE
Systemic lupus erythematosus
2.1. Mannose binding lectin is a biomarker of SLE disease activity A role for mannose binding lectin (MBL) in autoimmune diseases has been demonstrated earlier and elevated level of MBL has been shown in SLE patients. In a recent study MBL has been evaluated as a potential biomarker for disease activity in SLE. In this case control study SLE patients (93 females) and 67 age, sex, ethnicity matched healthy controls were enrolled. Plasma MBL levels were quantified by ELISA. Clinical, serological and other markers of disease activity (C3, C4 and anti-dsDNA) were measured by standard laboratory procedures. The study found that the mean plasma MBL levels were significantly high in SLE patients compared to healthy controls (P < 0.0001). MBL levels were variable in different clinical categories of SLE. Lower levels were associated with musculoskeletal and cutaneous manifestations (P ¼ 0.002), while higher and intermediate MBL levels were significantly associated with nephritis in combination with other systemic manifestations (P ¼ 0.01 and P ¼ 0.04 respectively). Plasma MBL correlated with SLEDAI (P ¼ 0.0003, r ¼ 0.36), anti-dsDNA (P < 0.0001, r ¼ 0.54), proteinuria (P < 0.0001, r ¼ 0.42) and negatively correlated with C3 (P ¼ 0.007, r ¼ 0.27) and C4 (P ¼ 0.01, r ¼ 0.29). Thus, plasma MBL is a promising marker in the assessment of SLE disease activity. (Arthritis Res Ther 2012;14:R218).
2.2. Long-term follow-up in lupus nephritis patients treated with rituximab shows good clinical and histopathological response A study to investigate the long-term clinical, histological and serological affects of B-cell-depleting therapy (BCDT) in patients with LN refractory to conventional treatment has been reported. 25 patients, followed for a mean time of 36 months, were included. Renal disease activity was evaluated with the BILAG index and renal response was determined according to the LN European consensus statement. Renal biopsies were performed for histological evaluation at baseline and followup. Partial response (PR) or complete renal response (CR) was observed in 22 of 25 after a median of 12 months. Sixteen patients achieved CR after a median of 24 months. Six patients
Antiphospholipid antibodies (aPL) play an active role in the pathogenesis of the antiphos-pholipid syndrome (APS). Primary prevention in APS may be aimed at decreasing existing elevated aPL levels, or preventing high aPL titres and/or lupus anticoagulant (LAC) from developing in the first place. Hydroxychloroquine (HCQ) has been shown in retrospective studies to decrease aPL titres in laboratory studies, and to decrease thrombosis risk in patients with SLE. A recent study has investigated an association between HCQ use and persistent aPL and/or LAC in SLE. This study identified all patients over 21 years old with SLE from an urban tertiary care centre who had aPL and LAC measured on at least 2 occasions at least 12 weeks apart. It defined the presence of persistent LACþ and/or at least 1 aPL 40 U [immunoglobulin A (IgA), IgG, or IgM] as the main outcome variable. Among 90 patients included in the study, 17 (19%) had persistent LACþ and/or at least 1 aPL 40 U. HCQ use was associated with significantly lower odds of having persistent LACþ and/or aPL 40 U (OR 0.21, 95% CI 0.05, 0.79, p ¼ 0.02), adjusted for age, ethnicity, and sex. This is the first study to show that HCQ use is associated with lower odds of having persistently positive LAC and/or aPL. (J Rheumatol 2013;40:30e33).
2.4. Vitamin D supplementation is recommended in patients with SLE Vitamin D has potent immunomodulatory properties that support its use in the treatment of autoimmune conditions, including SLE. A recent study assessed vitamin D status in patients with SLE and determined alterations in inflammatory and haemostatic markers and disease activity before and after vitamin D supplementation. 267 SLE patients were randomized 2:1 to receive either oral cholecalciferol 2000 IU/day or placebo for 12 months. Vitamin D levels were measured by Liaison immunoassay (normal 30e100 ng/ml). Serum levels between 10 and 30 ng/ml were classified as vitamin D insufficiency and levels < 10 ng/ml as vitamin D deficiency. The mean 25(OH)D level at baseline was 19.8 ng/ml in patients compared to 28.7 ng/ml in controls. The overall prevalence of suboptimal and deficient 25(OH)D serum levels among patients with SLE at
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baseline was 69% and 39%, respectively. Lower 25(OH)D levels correlated significantly with higher SLE disease activity. At 12 months of therapy, there was a significant improvement in levels of inflammatory and haemostatic markers as well as disease activity in the treatment group compared to the placebo group. Thus, this study concluded that Vitamin D supplementation in patients with SLE is recommended because increased vitamin D levels seem to ameliorate inflammatory and hemostatic markers and show a tendency towards subsequent clinical improvement. (J Rheumatol 2013;40:265e272).
WOMAC score were used to evaluate the efficacy of hyaluronic acid injections before and 3 and 6 months after treatment. Both treatment regimens resulted in a significant improvement versus baseline in all endpoints at 3 and 6 months ( p less than 0.001). Treatment with Variofill resulted in a high percentage improvement in Visual Analogue Scale pain, WOMAC score pain and physical activity, when compared to Synvisc viscosupplementation, at 6 months ( p less than 0.05). These results are encouraging for larger clinical trials with Variofill in larger cohorts of patients affected by osteoarthritis of the knee. (Int J Immunopathol Pharmacol. 2012;25:1093e1098).
3.
3.3. Strontium ranelate could be the first structure modifying drug for treatment of knee osteoarthritis
Osteoarthritis
3.1. Idiopathic hand osteoarthritis and haemochromatosis arthropathy differ significantly Haemochromatosis arthropathy is a secondary OA and the most frequent and earliest clinical presentation of hereditary haemochromatosis (HH). The aim of a recent study was to perform a direct clinical, functional and radiographic comparison with idiopathic hand OA (HOA) to unravel important differences between these clinical entities. In total, 299 patients (141 with HH arthropathy of the hands and 158 patients with idiopathic HOA) were recruited. It was seen that HH arthropathy and HOA differed significantly: patients with HH arthropathy were younger and predominantly male as compared with HOA. In males but not females, HH arthropathy led to an earlier start of symptoms than in HOA. Patients with HOA had more tender joints and worse hand function than patients with HH arthropathy, although subjective measures of joint pain and function were similar. MCP and wrist joint involvement was more frequent and severe in HH arthropathy, while HOA patients more frequently had degenerative changes in the first CMC as well as PIP and DIP joints. Thus, HH arthropathy and idiopathic HOA differ significantly in terms of epidemiology, localization, severity of symptoms and radiographic changes. (Rheumatology. Advance Access published January 12, 2013).
3.2. Viscosupplementation with a new highly crosslinked hyaluronic acid may be better than that with the widely used Synvisc in knee OA Osteoarthritis is characterized by progressive articular cartilage degeneration, changes in subchondral bone and synovial inflammation, leading to pain and disability. Viscosupplementation with hyaluronic acid has been widely investigated due to the viscoelastic properties of this compound to manage pain improving the ability to perform daily activities in patients affected by osteoarthritis. A recent study has investigated the clinical effectiveness of viscosupplementation with a new highly cross-linked hyaluronic acid, Variofill, in patients affected by bilateral knee osteoarthritis in comparison with the widely used Synvisc. A total of 20 patients, aged between 24 and 74 years and affected by bilateral knee osteoarthritis, participated in this pilot randomized triple-blind clinical study. They received two injections (2 ml each) of Synvisc in their left knee and 2 injections (2 ml each) of Variofill in their right knee spaced 15 days apart. Visual Analogue Scale and
Background strontium ranelate is currently used for osteoporosis. The international, double-blind, randomised, placebo-controlled Strontium ranelate Efficacy in Knee Osteoarthritis trial evaluated its effect on radiological progression of knee osteoarthritis. Patients with knee osteoarthritis (OA) (Kellgren and Lawrence grade 2 or 3, and joint space width (JSW) 2.5e5 mm) were randomly allocated to strontium ranelate 1 g/day (n ¼ 558), 2 g/day (n ¼ 566) or placebo (n ¼ 559). The primary endpoint was radiographical change in JSW (medial tibiofemoral compartment) over 3 years versus placebo. Secondary endpoints included radiological progression, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and knee pain. The intention-to-treat population included 1371 patients. Treatment with strontium ranelate was associated with smaller degradations in JSW than placebo (1 g/day: 0.23 (SD 0.56) mm; 2 g/day: 0.27 (SD 0.63) mm; placebo: 0.37 (SD 0.59) mm); treatmentplacebo differences were 0.14 (SE 0.04), 95% CI 0.05e0.23, p < 0.001 for 1 g/day and 0.10 (SE 0.04), 95% CI 0.02e0.19, p ¼ 0.018 for 2 g/day. Fewer radiological progressors were observed with strontium ranelate ( p < 0.001 and p ¼ 0.012 for 1 and 2 g/day). There were greater reductions in total WOMAC score ( p ¼ 0.045), pain subscore ( p ¼ 0.028), physical function subscore ( p ¼ 0.099) and knee pain ( p ¼ 0.065) with strontium ranelate 2 g/day. Strontium ranelate was well tolerated. Thus, treatment with strontium ranelate 1 and 2 g/day is associated with a significant effect on structure in patients with knee OA, and a beneficial effect on symptoms for strontium ranelate 2 g/day. (Ann Rheum Dis 2013;72:179e186).
3.4.
Methotrexate for pain relief in knee osteoarthritis?
Synovitis is very common in knee OA and associated with pain. An open-label study has evaluated an anti-synovitis therapy, MTX, for pain relief in knee OA. Inclusion criteria included pain visual analogue scale (VAS) > 40/100 mm, ACR clinical criteria for knee OA and intolerance/inefficacy of NSAID and opioids. US at baseline and 24 weeks assessed effusion and synovial thickness. Patients received MTX up to 20 mg/week for 24 weeks. 30 participants were recruited; mean age 64.5 years, median pain VAS 68 mm. At 24 weeks, 43% achieved 30% reduction in pain VAS, 23% achieved 50% reduction and 13% had worsened. 13 OARSI responder criteria. All had effusion/ synovitis at baseline. There was no correlation between change in imaging and change in pain scores at 24 weeks. This
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open-label trial suggests analgesic efficacy for MTX in OA knee and recommends that a randomized controlled trial is warranted. (Rheumatology. 2013 Jan 7 [Epub ahead of print]).
4.
Complex regional pain syndrome
4.1. In patients with CRPS-I, four i.v. infusions of neridronate 100 mg are associated with clinically relevant and persistent benefits Complex regional pain syndrome type I (CRPS-I) is a severely disabling pain syndrome for which no definite treatment has been established. The aim of a recent multi-centre, randomized, double-blind placebo-controlled trial was to test the efficacy of the amino-bisphosphonate neridronate in patients with CRP-I. 82 patients with CRP-I at either hand or foot were randomly assigned to i.v. infusion of 100 mg neridronate given four times over 10 days or placebo. After 50 days the former placebo patients were given open-label the same regimen of neridronate. Within the first 20 days, visual analogue scale (VAS) score decreased significantly more in the neridronate group. In the following 20 days, VAS remained unchanged in the placebo group and further decreased in the active group by 46.5 mm versus 22.6 mm for placebo group (P < 0.0001). Significant improvements versus placebo were observed also for a number of other indices of pain and quality of life. During the open-extension phase in the formerly placebo group the results of treatment were superimposable on those seen during the blind phase in the active group. A year later none of the patients had symptoms linked to CRPS-I. Thus, in patients with acute CRPS-I, four i.v. infusions of neridronate 100 mg are associated with clinically relevant and persistent benefits. These results provide conclusive evidence that the use of bisphosphonates, at appropriate doses, is the treatment of choice for CRPS-I. (Rheumatology 2013;52:534e542).
5.
NSAIDs
5.1. Triple therapy combination of diuretics with angiotensin converting enzyme inhibitors or angiotensin receptor blockers and NSAIDs is associated with an increased risk of acute kidney injury A study has assessed whether or not a double therapy combination consisting of diuretics, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers with addition of NSAIDs and the triple therapy combination of two of the aforementioned antihypertensive drugs to which NSAIDs are added are associated with an increased risk of acute kidney injury. A cohort of 487,372 users of antihypertensive drugs participated in this study. The main outcome measures were rate ratios with 95% confidence intervals of acute kidney injury associated with current use of double and triple therapy combinations of antihypertensive drugs with NSAIDs. During a mean follow-up of 5.9 years, 2215 cases of acute kidney injury were identified (incidence rate 7/10,000 person years). Overall, current use of a double therapy combination containing either diuretics or angiotensin converting enzyme inhibitors or
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angiotensin receptor blockers with NSAIDs was not associated with an increased rate of acute kidney injury. In contrast, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio 1.31, 95% confidence interval 1.12e1.53). In secondary analyses, the highest risk was observed in the first 30 days of use (rate ratio 1.82, 1.35e2.46). Thus, a triple therapy combination consisting of diuretics with angiotensin converting enzyme inhibitors or angiotensin receptor blockers and NSAIDs was associated with an increased risk of acute kidney injury. The risk was greatest at the start of treatment. Although antihypertensive drugs have cardiovascular benefits, vigilance may be warranted when they are used concurrently with NSAIDs. (BMJ 2013;346:e8525).
6.
Juvenile idiopathic arthritis
6.1. Ultrasound-detected synovial abnormalities are frequent in clinically inactive JIA, but do not predict a flare of synovitis To investigate whether children with JIA in clinical remission have subclinical synovial disease on ultrasound, and whether ultrasound abnormalities predict an early flare of synovitis, 39 consecutive children who had clinically defined inactive disease (ID) for a minimum of3 months underwent ultrasound assessment of 52 joints. All joints were scanned for synovial hyperplasia, joint effusion, power Doppler (PD) signal and tenosynovitis. Patients were then followed clinically for up to 2 years until a flare of synovitis occurred in one or more joints or until the 2-year visit if the disease remained in clinical remission. It was found that synovial hyperplasia, joint effusion, PD signal and tenosynovitis in at least one joint were detected in 76.9%, 66.7%, 33.3% and 15.4% of patients, respectively. During the 2-year follow-up, 24 patients (61.5%) experienced sustained ID, whereas 15 patients (38.5%) had a flare of synovitis in a total of 45 joints after a median of 10.6 months (range 6.3e13.7 months). At study entry, the rate of synovial hyperplasia, joint effusion and tenosynovitis was comparable between patients with persistent ID and patients with synovitis flare, whereas patients with persistent ID had a greater frequency of PD signal than patients with synovitis flare. Only 17 of the 45 flared joints had ultrasound abnormalities at study entry. Thus, this study found that ultrasound-detected synovial abnormalities are common in children with JIA in clinical remission. However, the presence of ultrasound pathology does not predict an early flare of synovitis in the affected joints. (Ann Rheum Dis 2013;72:223e228).
7.
Ankylosing spondylitis
7.1. Early inflammatory lesions may resolve without new bone formation in ankylosing spondylitis: a window of opportunity Although MRI data supports a link between spinal inflammation and formation of new bone in ankylosing spondylitis, anti-TNFa therapies have not been shown to prevent new bone formation. A new study aimed to demonstrate that while
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acute lesions resolve completely, more advanced lesions, characterised by evidence of reparation, are associated with new bone formation. In this study, MRI scans were performed at baseline, 12 and 52 weeks in 76 ankylosing spondylitis patients recruited to a placebo-controlled trial of adalimumab therapy. New syndesmophytes were assessed on lateral radiographs of the cervical and lumbar spine at baseline and 104 weeks. Anonymised MRI scans were read independently by two readers who recorded the presence/absence of acute (type A) and advanced (type B) vertebral corner inflammatory lesions (CIL) and fat lesions. New syndesmophytes developed significantly more frequently from type B CIL (16.7%) compared with type A CIL (2.9%) ( p ¼ 0.002) or no CIL (2.5%) ( p < 0.0001). This was also observed for both baseline and new vertebral corner fat lesions evolving over 52 weeks (11.1% ( p < 0.001) and 6.8% ( p ¼ 0.03), respectively). The association with type B CIL and fat was significant after adjustment for the extent of syndesmophytes/ankylosis at baseline. The data supports the hypothesis that new bone formation is more likely in advanced inflammatory lesions and proceeds through a process of fat metaplasia, supporting a window of opportunity for disease modification. Early inflammatory lesions may resolve without sequelae, while resolution of inflammation in more advanced inflammatory lesions, where reparative changes are already evident, is accompanied by new bone formation. (Ann Rheum Dis 2013;72:23e28).
8.
Inflammatory myopathy
antisynthetase syndrome with corticosteroid-refractory interstitial lung disease (ILD). Prednisone was the first-line treatment in all cases (1 mg/kg/ day orally, then tapering after 1 year). Patients with corticosteroid-refractory or relapsing ILD were then included in this retrospective study. All patients started CYC (3 mg/kg/ day) without increasing prednisone dosage. Both PFT and chest HRCT were regularly reassessed during follow-up. 18 patients with antisynthetase syndrome were evaluated; 17 had ILD (13 women; median age at ILD onset 57 yrs); all patients failed prednisone within 12 months of ILD onset and subsequently started CYC. The median follow-up on CYC was 96 months. Upon starting CYC, median forced vital capacity (FVC) was 60%, median DLCO 60%, and median Kazerooni score for ILD by HRCT chest16 (IQR 7e18). After 1 year of CYC, FVC ( p ¼ 0.0006), DLCO ( p ¼ 0.0010), and total Kazerooni score ( p ¼ 0.0002) improved and prednisone was tapered (median reduced from 25 mg/day to 2.5 mg/day; p < 0.0001). The results were substantially maintained including at last available follow-up. CYC side effects were hypertension (5 patients) and creatinine increase (6 patients). CYC was reduced in 3 cases and withdrawn in 4. Three out of 4 patients who interrupted CYC experienced ILD relapse; 2 patients recommenced lowdose CYC with subsequent ILD control. One patient refused re-treatment and subsequently died. The authors of this study conclude that CYC is effective and substantially safe in patients with anti-Jo1 antisynthetase syndrome with corticosteroid-refractory ILD. CYC withdrawal may be associated with ILD relapse, and low-dose CYC is effective in ILD control. (J Rheumatol First Release Feb 15 2013).
8.1. Patients with idiopathic inflammatory myopathies have low serum levels of vitamin D
9. In a study designed to compare serum levels of 25(OH) vitamin D in patients with idiopathic inflammatory myopathies (IIM) (polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM) and juvenile DM (JDM)) with healthy controls, serum samples from 149 patients with IIM and 290 healthy controls were analysed for 25(OH) vitamin D. Patients with IIM had significantly lower serum levels of 25(OH) vitamin D than healthy controls (median 39 (10e168) nmol/l versus 68 (19e197) nmol/l; p ¼ 0.0001). There was no significant difference in vitamin D levels between the myositis subgroups. When vitamin D levels were subclassified into deficient (<50 nmol/l), insufficient (50e74 nmol/l) and normal (75 nmol/l),most of the patients with PM (68%), DM (65%) and IBM (53%) had deficient levels compared with only 60 (21%) healthy individuals. In patients with IIM the OR for deficient versus normal was 17.7 and the OR for insufficient versus normal was 2.4. Thus, low serum levels of vitamin D were found in most patients with IIM and may confer a risk factor for developing adult myositis, similar to some other autoimmune diseases. (Ann Rheum Dis 2013;72:512e516).
8.2. Cyclosporine is effective and safe in anti-Jo1positive patients with corticosteroid-refractory interstitial lung disease A study has described the long-term effectiveness and safety of cyclosporine (CYC) in patients with anti-Jo1-positive
ANA testing
9.1. More than 90% of patients referred to a rheumatology clinic for a positive ANA test result have no evidence for an ANA-associated rheumatic disease A retrospective study investigated the clinical utility of a positive ANA test performed outside of the rheumatology setting. Prior studies have investigated the frequency of ANA positivity within the general population. The purpose of this investigation was to evaluate the clinical utility of a positive ANA test result in a real-world setting by reviewing the final diagnoses of patients who were referred to a tertiary rheumatology clinic for evaluation of a positive ANA test result. A total of 232 patients were referred for a positive ANA test result. The positive predictive value of a positive ANA test result in this cohort was 2.1% for lupus and 9.1% for any ANAassociated rheumatic disease. No ANA-associated rheumatic disease was identified in patients with an ANA < 1:160. The most common reason for ordering ANA testing was widespread pain and tenderness (23.2%). Thus, in this retrospective study, more than 90% of patients who were referred to a tertiary rheumatology clinic for a positive ANA test result had no evidence for an ANA-associated rheumatic disease. The poor predictive value of a positive ANA in this cohort was largely attributable to unnecessary testing in patients with low pretest probabilities for ANA-associated rheumatic disease. (Am J Med 2013;126:342e348).
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10.
Patient-reported outcome measures
10.1. Patients completing patient-reported outcome measures may not be able to understand what they are answering and may be unable to give an accurate perspective on their condition A study to assess the reading levels required to complete 10 patient-reported outcome measures (PROs) commonly used in rheumatology clinical and research settings has been reported. Four reviewers critiqued each measure blindly using two standardized readability indexes and a final readability score for each PRO was agreed. Only six of the PROs met the
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recommended reading level for health education literature. Thus, many people completing PROs will not be able to understand what they are answering and will be unable to give an accurate perspective on their condition. PROs in rheumatology should avoid using complicated words so that patients can understand and provide valid responses. (Rheumatology 2013;52:460e464).
Conflicts of interest The author has none to declare.
Answers to Rheumatology Quiz
1a*, 2b**, 3c***, 4cy, 5byy, 6cyyy, 7dx, 8bxx, 9dxxx, 10d{
* In 1930, Benediktos Adamantiades, a Greek ophthalmologist described “A case of relapsing iritis with hypopyon” in a 20-year old man with the three cardinal signs of the disease e genital ulcers, arthritis, and the ocular signs. In 1937, Hulusi Behcet, a dermatologist from Turkey described three patients with oral and genital ulcerations and hypopyon uveitis. ** Although anterior uveitis was described in the initial patients, posterior uveitis is the hallmark lesion of BD. *** Acneiform nodules in BD can be present over any part of the body; they may not always be hair follicle associated; skin biopsy in BD lesions shows an inflammatory infiltrate. y Brain. 1999;122:2183e2194. yy Named after two British physicians, John Patterson Hughes and Peter George Ingle Stovin, who first described it in 1959. Presents with fever and hemoptysis. yyy Pulmonary embolism is uncommon in BD; arterial aneurysms are superficial “arterial aphthae”. x All the other lesions have also been reported in BD. xx Erythematous papule or pustule formation at a skin site 24e48 h following insertion of a needle into the skin. xxx MAGIC ¼ mouth and genital ulcerations with inflamed cartilage has features of both BD and RP. { Non-erosive, non-deforming oligoarthritis which responds well to colchicine. Azathioprine and TNF inhibitors are used for refractory arthritis.